Utilization of dialkylfumarates

ABSTRACT

The present invention relates to the use of certain dialkyl fumarates for the preparation of pharmaceutical preparations for use in transplantation medicine or for the therapy of autoimmune diseases and said compositions in the form of micro-tablets or pellets. For this purpose, the dialkyl fumarates may also be used in combination with conventional preparations used in transplantation medicine and immunosuppressive agents, especially cyclosporines.

REFERENCE TO RELATED APPLICATIONS

This application is a continuation of application Ser. No. 10/197,077,filed Jul. 17, 2002, which is a Division of commonly-owned applicationSer. No. 09/831,620, filed May 10, 2001 now U.S. Pat. No. 6,509,376,which is a 371 continuation of PCT Application PCT/EP99/08215, filedOct. 29, 1999, the text of which is not in English, which PCTApplication claims priority on German Application No. 198 53 487.6,filed Nov. 19, 1998, the text of which is not in English, all of whichare incorporated herein by reference.

DESCRIPTION

The present invention relates to the use of dialkyl fumarates forpreparing pharmaceutical preparations for use in transplantationmedicine or the therapy of autoimmune diseases and pharmaceuticalpreparations in the form of micro-tablets or micro-pellets containingdialkyl fumarates.

On the one hand, therefore, it relates especially to the use of dialkylfumarates for preparing pharmaceutical preparations for the treatment,reduction or suppression of rejection reactions of the transplant by therecipient, i.e. host-versus graft reactions, or rejection of therecipient by the transplant, i.e. graft-versus-host reactions. On theother hand, it relates to the use of dialkyl fumarates for preparingpharmaceutical preparations for treating autoimmune diseases such aspolyarthritis, multiple sclerosis, juvenile-onset diabetes, Hashimoto'sthyroiditis, Grave's disease, systemic Lupus erythematodes (SLE),Sjogren's syndrome, pernicious anaemia and chronic active (=lupoid)hepatitis.

Both graft rejection and autoimmune diseases are based on medicallyundesirable reactions or dysregulation of the immune system. Cytokinssuch as interleukins or tumour necrose factor α (TNF-α) are substantialmediators influencing the immune system. In general, both are treated bythe administration of immunosuppressive agents such as cyclosporine.

In the overall result, autoimmune diseases may be defined as the failureof the tolerance of endogenic substances or antigens. As a rule, thistolerance can be maintained only if the antigens keep coming intocontact with immunological cells. When this tolerance is lost,autoantibodies are formed, i.e. a humoral immunoresponse againstendogenic tissue. The exact nature of the involvement of TNF-α is notknown.

Transplantations are tissue or organ transplantations, i.e. the transferof tissues such as cornea, skin, bones (bone chips), vessels or fasciae,of organs such as kidney, heart, liver, lung, pancreas or intestines, orof individual cells such as islet cells, α-cells and liver cells, thekidney having the greatest significance as a transplanted organ.

According to the degree of relationship between the donor and therecipient we differentiate between autotransplantation (transfer toanother part of the body of the same individual), iso-transplantation(transfer to another, genetically identical individual) and allogenictransplantation (transfer to another individual of the same species).Depending on the site of origin and transplantation, we furtherdifferentiate between homotopic transplantation (transfer to the samesite) and heterotopic transplantation (transfer to a different site).The above-mentioned transplantations play an important role in modernmedicine.

A major problem in transplantation medicine is graft rejection aftertransplantation of the tissue, organ or cell by immunological defensereactions of the recipient. Such a graft rejection is also calledhost-versus-graft reaction. The immunological defense reaction of theorganism against the heteroprotein often results in rejection ordissolution of the grafts. In host-verses-graft reactions, differentstages may be distinguished. Depending on the degree of differencebetween the recipient and the donor, this reaction takes place atdifferent speeds so that we speak of an acute, sub-acute or chronicreaction. The acute rejection process is accompanied by the irreversibleloss of the transplant (necrotisation) as a result of arteriitis orarteriolitis within 48 hours and cannot be influenced by theadministration of drugs. The sub-acute rejection reaction becomesmanifest as a rejection crisis from day 12 to month 4 with reversiblefunctional disorders as a result of a transplant vasculopathy. Finally,the loss of function of the transplant as a result of vascular changessuch as obliterating arteriopathy, which proceeds over weeks or yearsand can practically not be influenced by drugs, is termed a chronicrejection reaction.

Vice-versa, rejection reactions of the transplant against the recipient,the so-called graft-versus-host reactions, may occur whenimmunocompetent tissues are transplanted, i.e. primarily in bone marrowtransplantation. Again, the severity of the reaction is graded, andsubstantially similar complications result as inhost-versus-graft-reactions, namely arteriopathies and necroses.

To avoid such rejection reactions, i.e. the host-versus-graft reactionand the graft-versus-host reaction, transplantation medicine essentiallymakes use of immunosuppression, i.e. a weakening of the normalimmunoresponse. For this purpose, anti-lymphocyte sera are often used incombination with corticosteroids and so-called anti-metabolites, e.g.purine analogues such as 6-mercaptopurine and thioguanine which affectthe nucleic acid and protein synthesis and thus prevent cell divisionand proliferation. This leads to suppression of the production ofantibodies and the cellular immune response. The immunosuppressiveagents used for therapy are substances which suppress or weaken theimmunoreaction in the body either specifically or non-specifically.Non-specific immunosuppressive agents are cytostatic agents such as, forexample, alkylating agents or antimetabolites.

In addition, active ingredients are known which cause at least partialspecific immunosuppression, such as corticosteroids, antisera,antibodies FK-506, tacrolimus, mycophenolatemofetil and primarilycyclosporines such as cyclosporine A. As a result of using modernimmunosuppressive agents, the most important representatives of whichare the cyclosporines, especially cyclosporine A, it was possible toimprove the results of transplantation considerably over the last fewyears. At present, the survival rate after one year is about 60% forliver transplantations, about 80% for heart transplantations and over90% for kidney transplantations.

Autoimmune diseases where the endogenic immune system attacks endogenicorgans, tissues and cells are comparable to graft-versus-host reactions.These are also medically undesirable reactions of the immune systemwhich may be treated with immunosuppressive agents, too.

The danger in using immunosuppressive agents lies in weakening thebody's defense against infectious diseases and the increased risk ofmalignant diseases. Therefore, it is the object of the invention toprovide a pharmaceutical preparation to be employed in transplantationmedicine which may be used to treat, especially to suppress, weakenand/or alleviate host-versus-graft reactions and graft-versus-hostreactions, but does not have the above disadvantage.

It is another object of the invention to provide a pharmaceuticalpreparation which may be employed for treating autoimmune diseases,particularly polyarthritis, multiple sclerosis, juvenile-onset diabetes,Hashimoto's thyroiditis, Grave's disease, systemic Lupus erythematodes(SLE), Sjogren's syndrome, pernicious anaemia and chronic active(=lupoid) hepatitis, without the disadvantages of immunosuppression.

The object of the invention is achieved by using certain dialkylfumarates for preparing pharmaceutical preparations for use intransplantation medicine and for the therapy of autoimmune diseases andpharmaceutical preparations in the form of micro-tablets andmicro-pellets containing these dialkyl fumarates. The individual subjectmatters of the invention are characterized in detail in the claims. Thepreparations according to the invention do not contain any free fumaricacids per se.

It is known that pharmaceutical preparations which, upon biologicaldegradation after administration, enter into the citric acid cycle orare part thereof gain increasing therapeutic significance—especiallywhen given in high dosages—since they can alleviate or heal diseasescaused cryptogenetically.

Fumaric acid, for example, inhibits the growth of the Ehrlich ascitestumour in mice, reduces the toxic effects of mitomycin C and aflatoxinand displays antipsoriatic and anti-microbial activity. Whenadministered parenterally, transdermally and especially perorally, highdosages of fumaric acid or its derivatives known so far such asdihydroxyl fumaric acid, fumaramide and fumaronitrile have suchunacceptably severe side effects and high toxicity that, in most cases,such a therapy had to be abandoned in the past.

Surprisingly, investigations carried out by the applicant have shownthat methyl hydrogen fumarate, a metabolite of the dimethyl fumarate,initially increases the endotoxin-stimulated TNF-α secretion in humanmononuclear cells of periphere blood (periphere blood mononuclearcells=PBMC cells) and in isolated monocytes. In addition, the applicantwas able to show that fumaric acid has an effect on in vitro and in vivohaemagglutination which is comparable to that of cyclosporine.

Surprisingly, it has now been found that dialkyl fumarates areadvantageous for preparing pharmaceutical compositions for use intransplantation medicine and for the therapy of autoimmune diseases.This is because compositions containing such dialkyl fumaratessurprisingly permit a positive modulation of the immune system inhost-versus-graft reactions, graft-versus-host reactions and otherautoimmune diseases.

European Patent Application 0188 749 already describes fumaric acidderivatives and pharmaceutical compositions containing the same for thetreatment of psoriasis. Pharmaceutical compositions for the treatment ofpsoriasis containing a mixture of fumaric acid and other fumaric acidderivatives are known from DE-A-25 30 372. The content of free fumaricacid is obligatory for these medicaments.

DE-A-26 21 214 describes medicaments containing the fumaric acidmonoethyl ester and its mineral salts as active ingredient for thetreatment of psoriasis. The publication “Hautarzt (Dermatologist) (1987)279-285” discusses the use of fumaric acid monoethyl ester salts.Pharmaceutical preparations containing a mixture of fumaric acidmonoalkyl ester salts and a fumaric acid diester for the treatment ofpsoriasis, psoriatic arthritis, neurodermatitis and enteritis regionalisCrohn are known from EP 0 312 697 B1.

Specifically, the object of the invention is achieved by the use of oneor more dialkyl fumarates of the formula

wherein R₁ and R₂, which may be the same or different, independentlyrepresent a linear, branched or cyclic, saturated or unsaturated C₁₋₂₀alkyl radical which may be optionally substituted with halogen (Cl, F,I, Br), hydroxy, C₁₋₄ alkoxy, nitro or cyano for preparing apharmaceutical preparation for use in transplantation medicine or forthe therapy of autoimmune diseases.

The C₁₋₂₀ alkyl radicals, preferably C₁₋₈ alkyl radicals, mostpreferably C₁₋₅ alkyl radicals are, for example, methyl, ethyl,n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, pentyl, cyclopentyl,2-ethyl hexyl, hexyl, cyclohexyl, heptyl, cycloheptyl, octyl, vinyl,allyl, 2-hydroxyethyl, 2 or 3-hydroxy propyl, 2-methoxy ethyl, methoxymethyl or 2- or 3-methoxy propyl. Preferably at least one of theradicals R₁ or R₂ is C₁₋₅ alkyl, especially methyl or ethyl. Morepreferably, R₁ and R₂ are the same or different C₁₋₅ alkyl radicals suchas methyl, ethyl, n-propyl or t-butyl, methyl and ethyl being especiallypreferred. Most preferably, R₁ and R₂ are identical and are methyl orethyl. Especially preferred are the dimethyl fumarate, methyl ethylfumarate and diethyl fumarate.

The dialkyl fumarates to be used according to the invention are preparedby processes known in the art (see, for example, EP 0 312 697).

Preferably, the active ingredients are used for preparing oralpreparations in the form of tablets, micro-tablets, pellets orgranulates, optionally in capsules or sachets. Preparations in the formof micro-tablets or pellets, optionally filled in capsules or sachetsare preferred and are also a subject matter of the invention. The oralpreparations may be provided with an enteric coating. Capsules may besoft or hard gelatine capsules.

The dialkyl fumarates used according to the invention may be used aloneor as a mixture of several compounds, optionally in combination with thecustomary carriers and excipients. The amounts to be used are selectedin such a manner that the preparations obtained contain the activeingredient in an amount corresponding to 10 to 300 mg of fumaric acid.

Preferred preparations according to the invention contain a total amountof 10 to 300 mg of dimethyl fumarate and/or diethyl fumarate.

According to a preferred embodiment, the size or the mean diameter,respectively, of the pellets or micro-tablets is in the range from 300to 2,000 μm, especially in the range of 500 or 1,000 μm.

In addition to graft-versus-host reactions (see above), the followingautoimmune diseases to be treated may be named: polyarthritis, multiplesclerosis, graft-versus-host reactions, juvenile-onset diabetes,Hashimoto's thyroiditis, Grave's disease, systemic Lupus erythematodes(SLE), Sjogren's syndrome, pernicious anaemia and chronic active(lupoid) hepatitis. Autoimmune diseases in a wider meaning also comprisepsoriasis, psoriatic arthritis, neurodermatitis and enteritis regionalisCrohn.

In addition to the preparations for peroral administration in the formof micro-pellets, micro-tablets, capsules (such as soft and hardgelatine capsules), granulates and tablets cited above, suitablepharmaceutical preparations are preparations for cutaneous andtransdermal administration in the form of ointments, plasters, lotionsor shower preparations and for parenteral administration in the form ofaqueous micro-dispersions, oil-in-water emulsions or oily solutions forrectal administration of suppositories or micro-enemas. Pharmaceuticalpreparations in the form of micro-tablets or micro-pellets are preferredfor the therapy of all autoimmune diseases mentioned above, includingpsoriasis, psoriatic arthritis, neurodermatitis and enteritis regionalisCrohn and are also a subject matter of the invention.

According to the invention, a therapy with dialkyl fumarates may also becarried out in combination with one or more preparations of the tripledrug therapy customarily used in organ transplantations or withcyclosporine A alone. For this purpose, the preparations administeredmay contain a combination of the active ingredients in the known dosagesor amounts, respectively. Likewise, the combination therapy may consistof the parallel administration of separate preparations, by the same ordifferent routes. Optionally, the dosage of the active ingredientcontained in addition to the dose of the fumaric acid derivativeadministered in accordance with the invention may be reducedadvantageously.

Another embodiment of the use according to the invention is to alternatethe drug therapy with immunosuppressive agents such as cyclosporine insequence with an application of the above-mentioned dialkyl fumarate.This means that an application of fumaric acid derivatives as definedabove over one or more weeks may follow a cyclosporine therapy of one ormore weeks. This permits reduction of the Cyclosporine A dosageresulting in a considerable decrease of the rate of side effects inlong-term therapy.

By administration of the dialkyl fumarates in the form of micro-tablets,which is preferred, gastrointestinal irritations and side effects, whichare reduced already when conventional tablets are administered but isstill observed, may be further reduced vis-a-vis fumaric acidderivatives and salts.

It is presumed that, upon administration of conventional tablets, theingredients of the tablet are released in the intestine in aconcentration which is too high, causing local irritation of theintestinal mucous membrane. This local irritation results in ashort-term release of very high TNF-α concentrations which may beresponsible for the gastrointestinal side effects. In case ofapplication of enteric-coated micro-tablets in capsules, on the otherhand, very low local concentrations of the active ingredients in theintestinal epithelial cells are achieved. The micro-tablets areincrementally released by the stomach and passed into the smallintestine by peristaltic movements so that distribution of the activeingredients is improved.

This means that enteric-coated micro-tablets in the same dosage aredistributed already in the stomach and passed to the intestine inportions, where the active ingredients are released in smaller dosages.This avoids local irritation of the intestinal epithelial cells and therelease of TNF-α. It is assumed that this results in the improvedtolerance of micro-tablets in the gastrointestinal tract vis-a-visconventional tablets.

In addition, resorption is improved, because the dialkyl fumarates to beused according to the invention are not the active ingredient per se,but a so-called prodrug, which must be converted into the activeingredient in the body.

In order to illustrate the use according to the invention, differentexamples for preparing preferred drugs are given below.

PRODUCTION EXAMPLES

In principle, the oral preparations according to the invention in theform of tablets or micro-tablets may be prepared by classical tablettingprocesses. Instead of such classical tabletting processes, other methodsfor the preparation of tablets may be used, such as direct tablettingand processes for preparing solid dispersions in according with the meltmethod and the spray drying method.

The tablets may be provided with an enteric coating. The enteric coatingmay be applied in a classical coating pan or sprayed on or applied in afluidised bed apparatus. The tablet may also be provided with a filmcoat.

Example 1

Preparation of enteric-coated micro-tablets in capsules containing 120.0mg of dimethyl fumarate, which corresponds to 96 mg of fumaric acid

Taking the necessary precautions (breathing mask, gloves, protectiveclothing, etc.), 12.000 kg of dimethyl fumarate are crushed, mixed andhomogenized by means of a sieve 800. Then an excipient mixture with thefollowing composition is prepared: 17.50 kg of starch derivative(STA-RX® 1500), 0.30 kg of microcrystalline cellulose (Avicel® PH 101),0.75 kg of PVP (Kollidon® 120), 4.00 kg of Primogel®, 0.25 kg ofcolloidal silicic acid (Aerosil®). The active ingredient is added to theentire powder mixture, mixed, homogenized by means of a sieve 200,processed in the usual manner with a 2% aqueous solution of polyvidonpyrrolidone (Kollidon® K25) to obtain a binder granulate and then mixedin the dry state with the outer phase. Said outer phase consists of 0.50kg of Mg stearate and 1.50 kg of talcum.

Then the powder mixture is compressed in the usual manner to obtainconvex tablets having a gross weight of 10.0 mg and a diameter of 2.0mm.

One example to achieve resistance to gastric acid is to dissolve asolution of 2.250 kg of hydroxy propyl methyl cellulose phthalate(HPMCP, Pharmacoat® HP 50) in portions in a mixture of the followingsolvents: 13.00 1 of acetone, 13.50 1 of ethanol (94 wt.-%, denaturedwith 2% of ketone) and 1.50 1 of demineralised water. As a plasticiser,castor oil (0.240 kg) is added to the finished solution and applied inportions onto the tablet cores in the customary manner.

After drying is completed, a suspension of the following composition isapplied as a film coat in the same apparatus: 0.340 kg of talcum, 0.400kg of titanium(VI) oxide Cronus RN 56, 0.324 kg of coloured lacquerL-Rot-lack 86837, 4.800 kg of Eudragit E 12.5% and 0.120 kg ofpolyethylene glycol 6000, pH 11 XI in a solvent mixture of the followingcomposition: 8.170 kg of 2-propanol, 0.200 kg of demineralised water and0.600 kg of glycerine triacetate (Triacetin).

After that the enteric-coated micro-tablets are filled into hardgelatine capsules having a net weight of 400 mg and sealed.

Example 2

Preparation of enteric-coated micro-tablets in capsules containing 120.0mg of dimethyl fumarate, which corresponds to 96 mg of fumaric acid

12.000 kg of dimethyl fumarate are crushed and homogenized as above.Then an excipient mixture composed as follows is prepared: 23.20 kg ofmicrocrystalline cellulose (Avicel® PH 200), 3.00 kg of Croscarmellosesodium (AC-Di-SOL-SD-711), 2.50 kg of talcum, 0.10 kg of anhydroussilica (Aerosil® 200) and 1.00 kg of Mg stearate. The active ingredientis then added to the entire powder mixture and mixed homogenously. Bymeans of direct tabletting, the powder mixture is then pressed intoconvex tablets having a gross weight of 10.0 mg and a diameter of 2.00mm.

After that, a solution of 0.94 Eudragit® L in isopropanol is preparedwhich also contains 0.07 kg of dibutyl phthalate. This solution issprayed onto the tablet cores. After that, a dispersion of 17.32 kg ofEudragit® L D-55 and a mixture of 2.80 kg of microtalcum, 2.00 kg ofMacrogol 6000 and 0.07 kg of dimeticon in water is prepared and sprayedonto the cores.

Next, the enteric-coated micro-tablets are filled into hard gelatinecapsules having a net weight of 650 mg and sealed.

Example 3

Preparation of micro-pellets in capsules containing 50.0 mg of dimethylfumarate, which corresponds to 40 mg of fumaric acid

5.000 kg of dimethyl fumarate are crushed and homogenized as above. Inaddition, 21 of a 20% (m/v) polyvinyl pyrrolidone solution (KollidonK-30) in ethanol are prepared. 7.250 kg of nonpareilles pellets in acoating pan are sprayed with part of the Kollidon K-30 solution untilslightly humid. Then the active ingredient is added in portions untilthe pellets are dry. This procedure of humidification/drying iscontinued until all of the active ingredient mixture has been added.Then the pellets are moved around until completely dry.

After that, the pellets are filled into hard gelatine capsules (126.5 mgpellets/capsule).

Example 4

Preparation of enteric-coated capsules containing 110.0 mg of dimethylfumarate, which corresponds to 88 mg of fumaric acid

11.000 kg of dimethyl fumarate are intensely mixed in a mixtureconsisting of 14.00 kg of starch, 5.65 kg of lactose, 2.00 kg ofmicrocrystalline cellulose (Avicel®), 1.00 kg of polyvinyl pyrrolidone(Kollidon® 25) and 2.443 kg of Primogel® and, taking the necessaryprecautions (breathing mask, gloves, protective clothing), homogenizedby means of a sieve 800.

Using a 2% aqueous solution of polyvinyl pyrrolidone (Kollidon® K25),the entire powder mixture is processed into a binder granulate in thecustomary manner and mixed with the outer phase when dry. Said outerphase consists of 0.350 kg of colloidal silicic acid (Aerosil®), 0.500kg of Mg stearate and 1.500 kg of talcum. The homogenous mixture isfilled into suitable capsules in portions of 400 mg which are thenprovided with an enteric coating consisting of hydroxy propyl methylcellulose stearate and castor oil as plasticiser in the customarymanner. Instead of using hard gelatine capsules, the product may also befilled into suitable enteric-coated capsules consisting of a mixture ofcellulose acetate phthalate (CAP) and hydroxy propyl methyl cellulosephthalate (HPMCP).

In comparison with substances of the prior art such as cyclosporine,which may cause massive kidney disorders or diseases of thelymphoproliferative system, a therapy with fumaric acid derivativesaccording to the invention for the indications listed above rarelyresults in serious side effects.

Among other things, the immunosuppressive effect of cyclosporine iscaused by the inhibition of Th-1 cell formation. As in vitro experimentsof the applicant have shown, fumarates cause a shift of the cytokinepattern of the Th1 type to the cytokine pattern of the Th2 type.

Especially in view of the long-term therapy and prevention which isalways necessary in graft-versus-host reactions and host-versus-graftreactions or other autoimmune diseases such as multiple sclerosis, theunexpected effect of the use according to the invention is of thegreatest interest. In a combination therapy of cyclosporine with thefumaric acid derivatives, the toxic side effects of the former compoundsmay be unexpectedly reduced to a substantial degree. In addition, theuse according to the invention is also significant in the substitutionof the corticosteroid therapy of autoimmune diseases which is known tobe accompanied by severe side effects.

1. A method of treating multiple sclerosis comprising administering, toa patient in need of treatment for multiple sclerosis, an amount of apharmaceutical preparation effective for treating multiple sclerosis,the pharmaceutical preparation comprising at least one excipient or atleast one carrier or at least one combination thereof; and dimethylfumarate, methyl hydrogen fumarate, or a combination thereof.
 2. Themethod of claim 1, wherein the dimethyl fumarate, methyl hydrogenfumarate, or a combination thereof is present in an amount of from 10 to300 mg in the pharmaceutical preparation.
 3. The method of claim 1,wherein the dimethyl fumarate, methyl hydrogen fumarate, or acombination thereof is provided in one or more capsules.
 4. The methodof claim 1, the pharmaceutical preparation comprising a combination ofdimethyl fumarate and methyl hydrogen fumarate.
 5. The method of claim1, the pharmaceutical preparation comprising methyl hydrogen fumarate.6. The method of claim 1, the pharmaceutical preparation comprisingdimethyl fumarate.
 7. The method of claim 6, wherein at least 50 mg ofdimethyl fumarate is present in the pharmaceutical preparation.
 8. Themethod of claim 6, wherein at least 110 mg of dimethyl fumarate ispresent in the pharmaceutical preparation.
 9. The method of claim 6,wherein at least 120 mg of dimethyl fumarate is present in thepharmaceutical preparation.
 10. The method of claim 6, wherein 50 mg ofdimethyl fumarate is present in the pharmaceutical preparation.
 11. Themethod of claim 6, wherein 110 mg of dimethyl fumarate is present in thepharmaceutical preparation.
 12. The method of claim 6, wherein 120 mg ofdimethyl fumarate is present in the pharmaceutical preparation.
 13. Themethod of claim 1, wherein the pharmaceutical preparation is formulatedfor oral administration.
 14. The method of claim 1, wherein thepharmaceutical preparation is formulated as a solid dosage form.
 15. Themethod of claim 1, wherein the pharmaceutical preparation is formulatedas microtablets.
 16. The method of claim 15, wherein the microtabletsare provided in one or more capsules, wherein at least 50 mg of dimethylfumarate is present in each capsule.
 17. The method of claim 16, whereinat least 110 mg of dimethyl fumarate is present in each capsule.
 18. Themethod of claim 17, wherein at least 120 mg of dimethyl fumarate ispresent in each capsule.
 19. The method of claim 15, wherein themicrotablets are enteric-coated.
 20. The method of claim 19, wherein themicrotablets have a mean diameter in the range of 0.3 mm to 2.0 mm,exclusive of any coating on the microtablets.
 21. The method of claim20, wherein the microtablets have a mean diameter of 2.0 mm, exclusiveof any coating on the microtablets.
 22. The method of claim 1, thepharmaceutical preparation comprising at least one carrier.
 23. Themethod of claim 1, the pharmaceutical preparation comprising at leastone excipient.
 24. The method of claim 1, the pharmaceutical preparationcomprising at least one excipient and at least one carrier.